The use of lubricating gels to reduce frictional irritation and pain associated with the insertion of catheters and instruments is well known. When catheters, and in particular the indwelling catheter, or when instruments are introduced into a body cavity, a certain measure of tissue-trauma, pain and irritation results, but this is generally without clinical sequelae for most body cavities. A particular problem arises however, when such catheters and instruments are used to explore certain body cavities known to harbor, or to be exposed to pathogenic organisms as for example, the genito-urinary tract, particularly when such procedures requires the retention of the catheter or when multiple instrumentation is necessary in that microbial infection virtually always occurs.
The presence of pathogenic organisms, as well as other microbes residing in the male and female urethra is well documented and infections of the bladder and urinary tract occur at an inordinately high incidence despite the institution of rigorous aseptic operatively techniques and excellent nursing care, as well as in the presence of the administration of antibiotics and other germicides. New infections occur each time when microbial organisms from outside gain access to the bladder through the urethra. The pathogens most often involved are those resident in the patient's environment and these have been found to be identical to those isolated from the vagina, pudendum, anus and urethra of the individual, thus establishing an instrumental conduit action to be a contributory cause.
The normal tissue defense mechanisms usually prevent clinical infection by microbial invaders in the urethra and washout effect of urinary flow while voiding, together with the intrinsic antibacterial properties of the urethral and vesical mucosal enzymes, ordinarily eliminates the organisms before these become a thread to the individual. These normal defense mechanisms however, become inadequate under certain clinical situations such as, (1) trauma to the urethral meatus and urethra to result in a fertile medium for bacterial growth and for impairment of the antibacterial activity of the urothelium, (2) an overwhelming inocculum of bacteria delivered to the urethra over a period of time against which the defense mechanism are inadequate, such as fecal contamination of an indwelling catheter, (3) relatively obscure changes in the length or caliber of the urethra and atrophic changes in the urethral mucosa, and, (4) after repeated catheterization and instrumental exploration of the genito-urinary tract or when in-dwelling catheters are utilized, and genito-urinary infection almost always occurs.
This extremely high incidence of urethral and bladder infection after catheterization and/or instrumentation procedures has been directly attributed to tissue injury from the procedure, as well as a result of the microbial conduit effect provided by the catheter and/or instrument. The urethra has a high microbial population which reside mainly in the distil portion of the urethra, but as the proximal urethra is ascended, the microbial population decreases to the point where there are virtually no pathogens and/or microbes in the proximal urethra where it emerges from the bladder. The tissues of the bladder and proximal urethra are known to be essentially germ-free. The proliferation of infection following such instrumentation had been unexplained for years until it was shown that the natural body defenses and natural antimicrobial bodies are temporarily destroyed in the course of tissue-trauma associated with such instrumental exploratory procedures and infection soon followed. Thus, when airborne organism, together with resident microbes of the surrounding anogenital area are carried along the urethra by the penetrating device, the temporary absence of the natural antimicrobial tissue defenses, as a result of operative tissue-trauma, no longer accted to destroy these invaders and infection almost always occurred.
In the effort to reduce or eliminate this source of infection, various local-acting antiseptic and/or antibiotic preparations were utilized. The use of phenol ointments were tried, but soon rejected when problems of discomfort, pain and irritation occurred. The antibiotic lubricating gel approach also failed since the topically-active polymixin-benzalkonium antibiotic ointment products have a limited and incomplete antimicrobial spectrum giving rise to resistant strains of micro-organisms and placed the patent in new jeopardy.
It has long been established that iodine is perhaps the most effective and desirable topical antimicrobial agent and its pharmaceutical preparations enjoy wide-spread usage in clinical medicine, first-aid procedures and environmental antisepsis. Despite the wide use of iodine as a topical germicide, lubricating gel compositions intended for use with catheters and instruments, do not include iodine as the antimicrobial agent because of the well known, inherent limitations of iodine. Iodine is a strong corrosive, oxidizing agent possessing a high order of chemical reactivity which tends to interact with most catheters and instruments, as well as to destroy the stability of most pharmaceutical compositions, and in particular, colloidal lubricating gels. Furthermore, the high vapor pressure of iodine precludes its use in tight compartments, such as the urethra and body cavities such as the bladder. These inherent limitations, together with the known high acute toxicity and local irritation of iodine has limited its use in topical antiseptic preparations to virtually only the aqueous and/or alcoholic solution.
When the use of iodine as the germicidal agent in a colloidal lubricating gel is considered, further complications arise. The strong electrical properties of iodine rapidly modifies the colloidal properties of the gel to result in coagulation of the colloid, rendering such gels useless. Apart from the destructive physical/chemical role of iodine in neutralizing the electronic balance of the colloidal system, iodine cannot be used in a gel coming into contact with nitrogen-amino substances as would be present in the urine coating the urethra when the germicidal lubricating gel is used with catheters inserted into the genito-urinary tract, since iodine reacts with such amino compounds to produce chemical compounds of great hazard to humans.
The development of iodophor germicidal compounds constitued a marked advance in overcoming the general inherent biologic limitations of elemental iodine since this new class of compounds by virtue of their unique chemical and physical structure modified the physiologic behavior of iodine without changing its broad spectrum germicidal properties. An iodophor involves the formation of a chemical complex between an organic polymeric iodine carrier, as for example, polyvinylpyrrolidone, nonylphenoxypoly-(ethyleneoxy)ethanol, and other detergent organic polymer compounds, with elemental iodine so that the resultant formed iodophor complex possesses new and novel properties which differ from its component moieties.
The bond between the organic carrier and the elemental iodine is essentially ionic and there is a shift in the ultraviolet absorption spectrum of iodine as well as an increased aqueous solubility for iodine. Thus, while elemental iodine is soluble to the extent of 0.034 percent in water at 25.degree. C., it is soluble to the extent of 0.58 percent in a one percent aqueous solution of polyvinylpyrrolidone-iodine through the iodopher formation to result in polyvinylpyrrolidone-iodine. This 17-fold increase in the solubility of iodine by complexing with polyvinylpyrrolidone to form an iodophor compound enables the use of iodine as a safe and effective germicide in aqueous solution. This bond between polyvinylpyrrolidine and iodine is ionic in character and the iodine cannot be extracted using the usual iodine extracting solvents, i.e. carbontetrachloride, and also the vapor pressure of iodine is reduced essentially to zero.
Further proof of the modification of the noxious biologic properties of elemental iodine, through iodophor formations, is seen in the marked reduction in irritation and toxicity for the formed complex, when compared to that of elemental iodine. Polyvinylpyrrolidone-iodine has an LD.sub.50 of 1300 mg/kg whereas elemental iodine in water has an LD.sub.50 of 400 mg/kg. When the gross pathology is studied for two groups of treated animals with aqueous iodine solution and polyvinylpyrrolidone-iodine solution, those treated with polyvinylpyrrolidone-iodine showed no hemorrhage or other gross pathology, whereas all animals treated with the aqueous iodine solution exhibited hemorrhagic gastritis. Tests for ittitation on intact skin, damaged skin and the eyes, establish polyvinylpyrrolidone-iodine to be singularly free of noxious irritation whereas the conventional aqueous solution of iodine was markedly irritated.
Studies by in-vivo and in-vitro testing for microbicidal efficacy of polyvinylpyrrolidone-iodine established this agent to possess the full microbicidal spectrum of elemental iodine against micro-organisms. A similar chemical and therapeutic biologic profile was established for the iodophor complexes formed between a surface-active iodophor agent, as for example, nonylphenoxy-poly-(ethyleneoxy)-ethanol iodine and other surface-active iodophors, as for example, poly-(oxypropylene)-poly-(oxyethylene) copolymers which are known as Poloxamer-iodine complexes also demonstrate quantitative but not qualitative differences in the modification of physical and chemical properties of iodine although the microbiologic germicidal properties of iodine remained intact.
Pharmaceutical compositions for use as lubricating gels are prepared with certain carbohydrate polymer substances, as for example, cellulose derivatives such as methylcellulose, hydroxyalkylcellulose and carboxymethylcellulose, or vegetable gums, such as alginic acid, esters of alginic acid, tragacanth, and gum karaya, or mixtures of these to form aqueous colloidal dispersions in the form of a viscous gel. Such colloidal gels are applied to the surface of catheters and instruments prior to their insertion into a body cavity to provide lubricating slip and therefore must be compatible with the catheter or instrument.